ArticleProceedings of the National Academy of Sciences of the United States of America2012
Benzodiazepine treatment induces subtype-specific changes in GABA(A) receptor trafficking and decreases synaptic inhibition.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers, 1 of them a synthesis that pooled it.
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Who cites it
46 citing papers in PubMed, 1 synthesis or guideline pooled it, 88 citations in OpenAlex.
- Acupuncture for insomnia after stroke: a systematic review and meta-analysis.BMC complementary and alternative medicine · 2016Pooled it
- Diazepam modulates anterior cingulate glutamate levels in people at clinical high-risk for psychosis.The international journal of neuropsychopharmacology · 2026Trial
- Chronic Chrysin, but Not Diazepam, Induces Anxiolytic-like Effects Without Behavioral Tolerance.Molecules (Basel, Switzerland) · 2026Article
- Synaptic correlates of benzodiazepine tolerance.Molecular psychiatry · 2026Review
- Chronic Diazepam Reveals Excessive Homeostatic Gain in SOD1International journal of molecular sciences · 2026Article
- Targeting γ-aminobutyric acid type A receptors to mitigate perioperative neurocognitive disorders: a narrative review.British journal of anaesthesia · 2026Review
- Chronic benzodiazepine treatment triggers gephyrin scaffold destabilization and GABAFrontiers in cellular neuroscience · 2025Article
- GABA system as the cause and effect in early development.Neuroscience and biobehavioral reviews · 2024Review
- Association Between Hypnotics and Dementia: A Mini Narrative Review.Psychiatry investigation · 2024Article
- Long-term α5 GABA A receptor negative allosteric modulator treatment reduces NMDAR-mediated neuronal excitation and maintains basal neuronal inhibition.Neuropharmacology · 2023Article
- Understanding the mechanism of action and clinical effects of neuroactive steroids and GABAergic compounds in major depressive disorder.Translational psychiatry · 2023Review
- Is the Precipitation of Anxiety Symptoms Associated with Bolus Doses of Flumazenil a Barrier to Its Use at Low Continuous Doses in Benzodiazepine Withdrawal?Journal of clinical medicine · 2022Article
- The Yin and Yang of GABAergic and Glutamatergic Synaptic Plasticity: Opposites in Balance by Crosstalking Mechanisms.Frontiers in synaptic neuroscience · 2022Review
- Efficacy and Safety of Acupuncture in the Treatment of Poststroke Insomnia: A Systematic Review and Meta-Analysis of Twenty-Six Randomized Controlled Trials.Evidence-based complementary and alternative medicine : eCAM · 2022Review
- Sustained treatment with an α5 GABA A receptor negative allosteric modulator delays excitatory circuit development while maintaining GABAergic neurotransmission.Neuropharmacology · 2021Article
- Acupuncture combined with moxibustion for insomnia after stroke: A protocol for systematic review and meta analysis.Medicine · 2021Article
- Preclinical characterization of zuranolone (SAGE-217), a selective neuroactive steroid GABANeuropharmacology · 2020Article
- Acupuncture for post-stroke insomnia: A protocol for systematic review and meta-analysis.Medicine · 2020Article
- Regulation of GABAInternational journal of molecular sciences · 2020Review
- Voltage dependent allosteric modulation of IPSCs by benzodiazepines.Brain research · 2020Article
Corrections and comments
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Authors and funding
6 authors at 4 institutions in 3 countries.
Funding
Abstract
Benzodiazepines potentiate γ-aminobutyric acid type A receptor (GABA(A)R) activity and are widely prescribed to treat anxiety, insomnia, and seizure disorders. Unfortunately, clinical use of benzodiazepines (BZs) is severely limited by tolerance. The mechanisms leading to BZ tolerance are unknown. BZs bind at the interface between an α and γ subunit of GABA(A)Rs, preferentially enhancing synaptic receptors largely composed of α(1-3, 5), β3, and γ2 subunits. Using confocal imaging and patch-clamp approaches, we show that treatment with the BZ flurazepam decreases GABA(A)R surface levels and the efficacy of neuronal inhibition in hippocampal neurons. A dramatic decrease in surface and total levels of α2 subunit-containing GABA(A)Rs occurred within 24 h of flurazepam treatment, whereas GABA(A)Rs incorporating α1 subunits showed little alteration. The GABA(A)R surface depletion could be reversed by treatment with the BZ antagonist Ro 15-1788. Coincident with decreased GABA(A)R surface levels, flurazepam treatment reduced miniature inhibitory postsynaptic current amplitude, which returned to control levels with acute Ro 15-1788 treatment. GABA(A)R endocytosis and insertion rates were unchanged by flurazepam treatment. Treatment with leupeptin restored flurazepam lowered receptor surface levels, strongly suggesting that flurazepam increases lysosomal degradation of GABA(A)Rs. Together, these data suggest that flurazepam exposure enhances degradation of α2 subunit-containing GABA(A)Rs after their removal from the plasma membrane, leading to a reduction in inhibitory synapse size and number along with a decrease in the efficacy of synaptic inhibition. These reported subtype-specific changes in GABA(A)R trafficking provide significant mechanistic insight into the initial neuroadaptive responses occurring with BZ treatment.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.